Inhibition of angiogenesis and MMP-9 expression by PCK3145 is mediated through targeting of the Akt signaling pathway
Notice bibliographique
Résumé
Proc Amer Assoc Cancer Res, Volume 47, 2006 4369 Adenocarcinoma of the prostate gland is among the leading malignancies in men with high morbidity and mortality rates due to the development of skeletal metastases. PSP-94, one of the three predominant proteins produced by normal prostate gland, is absent in late stage prostate cancer which supports its potential tumor suppressor role. Previous studies carried out in our laboratory have shown the ability of PSP-94 and PCK3145 (amino acids 31–45 of PSP-94) to suppress prostate cancer growth and development of skeletal metastases. Recently, a phase IIa clinical trial carried out in patients with hormone refractory prostate cancer and treated with PCK3145 resulted in disease stabilization. Furthermore, treatment with PCK3145 caused either a stabilization or reduction of MMP-9 levels in these patients. In the current study we evaluated the possible mechanism(s) of action of PCK3145. For these studies, rat prostate cancer MatLyLu cells were treated with different concentrations of PCK3145. Total cellular RNA and conditioned media were collected. PCK3145 treatment resulted in a significant dose dependent reduction in MMP-9 mRNA and protein levels as analyzed by real time RT-PCR, Western blot analysis and zymography. No significant effect on MMP-2 production was seen. Furthermore, treatment of MatLyLu cells with different doses of PCK3145 resulted in a dose dependent reduction in the levels of p-Erk and p-Akt. For in vivo studies, male Copenhagen rats were inoculated either subcutaneously or via intracardiac injections with MatLyLu cells to develop primary tumor growth or experimental skeletal metastases, respectively. Animals were treated with different doses of PCK3145 (1.0–100.0μg/kg) and at the end of the study their tumors were excised and analyzed. PCK3145 caused a dose dependent reduction in tumor volume and a significant decrease in MMP-9 production and neovascularization as assessed by immunohistochemical analysis of primary tumors. These effects were due to the ability of PCK3145 to inhibit p-Erk and p-Akt production by primary tumors. Similarly PCK3145 treatment caused a significant reduction in skeletal tumor burden, delay in hind limb paralysis and inhibition of MMP-9 expression. Collectively, the results obtained from these studies show that the ability of PCK3145 to reduce tumor growth and delay the development of skeletal metastases is in part due to its ability to reduce the levels of MMP-9 and tumor angiogenesis, effects which are mediated through the reduction of active Akt kinase previously reported to modulate the expression of several genes including MMP-9. The results obtained from these studies provide evidence for the mechanism of action of PCK3145 which can be selectively targeted alone or in combination with other therapeutic agents for prostate cancer patients.
Récupéré en direct depuis OpenAlex et désinversé. Les résumés ne sont pas conservés dans cette base de données : les index inversés représentent 8,6 Go des 9,3 Go de texte de la base, et le serveur dispose de 13 Go libres.
Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,000 |
| Méta-épidémiologie (sens strict) | 0,001 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,000 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,000 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,001 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,002 | 0,001 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».